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Epstein-Barr Virus Latent Membrane Protein 1 Activation of NF-κB through IRAK1 and TRAF6
Micah Luftig, Efthimios Prinarakis, Teruhito Yasui, Theodore Tsichritzis, Ellen Cahir-McFarland, Jun-Ichiro Inoue, Hiroyasu Nakano, Tak Wah Mak, Wen-Chen Yeh, Xiaoxia Li, Shizuo Akira, Nobutaka Suzuki, Shinobu Suzuki, George Mosialos and Elliott Kieff
Proceedings of the National Academy of Sciences of the United States of America
Vol. 100, No. 26 (Dec. 23, 2003), pp. 15595-15600
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3149051
Page Count: 6
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Epstein-Barr virus latent membrane protein 1 (LMP1) activation of NF-κB is critical for Epstein-Barr virus-infected B lymphocyte survival. LMP1 activates the IκB kinase complex and NF-κB through two cytoplasmic signaling domains that engage tumor necrosis factor receptor-associated factor (TRAF)1/2/3/5 or TRADD and RIP. We now use cells lacking expression of TRAF2, TRAF5, TRAF6, IKKα, IKKβ, IKKγ, TAB2, IL-1 receptor-associated kinase (IRAK)1, or IRAK4 to assess their roles in LMP1-mediated NF-κB activation. LMP1-induced RelA nuclear translocation was similar in IKKα knockout (KO) and WT murine embryo fibroblasts (MEFs) but substantially deficient in IKKβ KO MEFs. NF-κB-dependent promoter responses were also substantially deficient in IKKβ KO MEFs but were hyperactive in IKKα KO MEFs. More surprisingly, NF-κB responses were near normal in TRAF2 and TRAF5 double-KO MEFs, IKKγ KO MEFs, TAB2 KO MEFs, and IRAK4 KO MEFs but were highly deficient in TRAF6 KO MEFs and IRAK1 KO HEK293 cells. Consistent with the importance of TRAF6, LMP1-induced NF-κB activation in HEK293 cells was inhibited by expression of dominant-negative TAB2 and Ubc13 alleles. These data extend a role for IKKα in IKKβ regulation, identify an unusual IKKβ-dependent and IKKγ-independent NF-κB activation, and indicate that IRAK1 and TRAF6 are essential for LMP1-induced NF-κB activation.
Proceedings of the National Academy of Sciences of the United States of America © 2003 National Academy of Sciences